title: Modulation of neuronal glutathione synthesis by EAAC1 and its interacting protein GTRAP3-18.
abstract: Glutathione (GSH) plays essential roles in different processes such as antioxidant defenses, cell signaling, cell proliferation, and apoptosis in the central nervous system. GSH is a tripeptide composed of glutamate, cysteine, and glycine. The concentration of cysteine in neurons is much lower than that of glutamate or glycine, so that cysteine is the rate-limiting substrate for neuronal GSH synthesis. Most neuronal cysteine uptake is mediated through the neuronal sodium-dependent glutamate transporter, known as excitatory amino acid carrier 1 (EAAC1). Glutamate transporters are vulnerable to oxidative stress and EAAC1 dysfunction impairs neuronal GSH synthesis by reducing cysteine uptake. This may start a vicious circle leading to neurodegeneration. Intracellular signaling molecules functionally regulate EAAC1. Glutamate transporter-associated protein 3-18 (GTRAP3-18) activation down-regulates EAAC1 function. Here, we focused on the interaction between EAAC1 and GTRAP3-18 at the plasma membrane to investigate their effects on neuronal GSH synthesis. Increased level of GTRAP3-18 protein induced a decrease in GSH level and, thereby, increased the vulnerability to oxidative stress, while decreased level of GTRAP3-18 protein induced an increase in GSH level in vitro. We also confirmed these results in vivo. Our studies demonstrate that GTRAP3-18 regulates neuronal GSH level by controlling the EAAC1-mediated uptake of cysteine.
authors.affiliation: Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8605, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Aoyama
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watabe
authors.forename: Toshio
authors.initials: T
authors.lastname: Nakaki
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism*; D005978:Glutathione / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D050580:Excitatory Amino Acid Transporter 3; D005978:Glutathione